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Duration and magnitude of nerve growth factor signaling depend on the ratio of p75 LNTR to TrkA
Author(s) -
Twiss Jeffery L.,
Wada H. Garrett,
Fok Katherine S.,
Chan Samuel D.H.,
Verity A. Neil,
Baxter Gregory T.,
Shooter Eric M.,
Sussman Howard H.
Publication year - 1998
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(19980215)51:4<442::aid-jnr4>3.0.co;2-c
Subject(s) - nerve growth factor , trk receptor , chinese hamster ovary cell , tropomyosin receptor kinase a , neurotrophin , extracellular , signal transduction , intracellular , receptor , biology , low affinity nerve growth factor receptor , microbiology and biotechnology , endocrinology , medicine , chemistry , biochemistry
The role of the low affinity neurotrophin receptor p75 LNTR in neurotrophin signal transduction remains open. Recent reports show that this receptor generates intracellular signals independent of Trk activity, and others imply that it collaborates with Trk(s) to enhance cellular responses to low neurotrophin concentrations. We have used the Cytosensor microphysiometer as a direct marker of intracellular metabolic activity to address the physiologic role of p75 LNTR in nerve growth factor (NGF) signal transduction. NGF treatment of PC12 or TrkA‐transfected Chinese hamster ovary (CHO) cells results in a rapid, transient increase in the extracellular acidification rate as measured by the Cytosensor; in both cell types, p75 LNTR enhances this response. p75 LNTR affects both the magnitude of and the duration of the extracellular acidification response to NGF. Moreover, it is not merely the presence of p75 LNTR , but also the ratio of p75 LNTR :TrkA which determines cellular responsiveness to NGF. In transiently transfected CHO cells, a 5:1 ratio of p75 LNTR :trkA cDNAs produced the greatest change in NGF‐induced acid secretion. Pretreatment of PC12 cells with anti‐p75 LNTR antibodies decreased the responsiveness to NGF. However, long‐term NGF exposure to PC12 cells in which p75 LNTR expression was decreased to approximately 10% of wild‐type levels showed a longer duration of acid secretion compared to wild‐type PC12 cells. Together, these data suggest that p75 LNTR may play a dual role in modulating NGF signal transduction by enhancing and extending cellular responses to short‐term ligand exposures while attenuating the metabolic response to long‐term ligand exposures. With regard to potential Trk‐independent p75 LNTR signal transduction mechanisms, we detected no change in extracellular acidification response in 75 LNTR ‐transfected CHO cells, PCNA‐15 fibroblasts, or Schwann cells, all of which express large amounts of p75 LNTR and no Trk. Thus, p75 LNTR cannot produce any signal detected by microphysiometry in the absence of TrkA. J. Neurosci. Res. 51:442–453, 1998. © 1998 Wiley‐Liss, Inc.